Download Different Outcomes between Cyclophosphamide Plus Horse or

Different Outcomes between Cyclophosphamide
Plus Horse or Rabbit Antithymocyte Globulin
for HLA-Identical Sibling Bone Marrow Transplant
in Severe Aplastic Anemia
Elias Hallack Atta,1 Adriana Martins de Sousa,1
Marcelo Ribeiro Schirmer,1 Luis Fernando Bouzas,1 Marcio Nucci,2 Eliana Abdelhay1
The standard regimen for HLA-identical sibling bone marrow transplant (BMT) in severe aplastic anemia
(SAA) is cyclophosphamide (Cy) and horse antithymocyte globulin (ATG). Horse ATG has been replaced
by rabbit ATG in many countries due to the unavailability of the former product. This study was designed
to assess if these ATG preparations are interchangeable in the preparative regimen for matched related
BMT in SAA. Forty consecutive BMTs were retrospectively analyzed: 20 received Cy plus horse ATG and
20 received Cy plus rabbit ATG as the preparative regimen. Conditioning with rabbit ATG was protective
against acute graft-versus-host disease (aGVHD) grades II-IV and moderate-severe chronic GVHD
(cGVHD), with incidence rates of 0% versus 35.2% (P 5 .009) and 0% versus 34.0% (P 5 .04), respectively.
On day 1100, the probability of proven/probable invasive fungal disease (IFD) was higher in patients conditioned with rabbit ATG, 31.2% versus 5.5%, respectively (P 5 .04). Earlier cytomegalovirus (CMV) reactivation (40 versus 50 days; P 5.02) was observed with rabbit ATG. An inferior lymphocyte count on days 130
(0.360 versus 0.814 109/L; P 5 .01) and 190 (0.744 versus 1.330 109/L; P 5 .006) was noticed in recipients of rabbit ATG. The incidence of stable mixed chimerism was higher in recipients of rabbit ATG (18.2%
versus 80%, respectively; P 5 .004). These results suggest that horse and rabbit ATG preparations have
different biological and clinical properties and should not be used interchangeably in the preparative regimen
for related BMT in SAA.
Biol Blood Marrow Transplant 18: 1876-1882 (2012) Ó 2012 American Society for Blood and Marrow Transplantation
KEY WORDS: Severe aplastic anemia, Preparative regimen, Antithymocyte globulin, Bone marrow
transplantation
INTRODUCTION
Allogeneic bone marrow transplant (BMT) remains the first-line treatment for patients with severe
aplastic anemia (SAA) younger than 40 years with an
HLA-identical sibling donor [1,2]. The current
standard preparative regimen for matched-related
BMT in SAA is high-dose cyclophosphamide (Cy)
and antithymocyte globulin (ATG) [1,2]. The
majority of studies that have evaluated this
From the 1CEMO, National Cancer Institute, Rio de Janeiro, Brazil;
and 2University Hospital, Universidade Federal do Rio de
Janeiro, Rio de Janeiro, Brazil.
Financial disclosure: See Acknowledgments on page 1881.
Correspondence and reprint requests: Marcio Nucci, MD,
Hematology Service, Hospital Universitario Clementino Fraga
Filho, Rua Prof. Rodolpho Paulo Rocco, 255, 4A12, Rio de Janeiro, RJ, Brazil 21941-913 (e-mail: [email protected]).
Received June 11, 2012; accepted July 3, 2012
Ó 2012 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
http://dx.doi.org/10.1016/j.bbmt.2012.07.004
1876
preparative regimen used the horse ATG preparation
[3-6]. Despite the lack of studies demonstrating the
interchangeability of different ATG preparations in
the conditioning regimen for BMT in SAA, horse
ATG has been replaced by rabbit ATG due to the
unavailability of the former drug in Latin America,
Europe, and Japan [1]. Regardless of some common
properties, rabbit ATG has a stronger lymphocytotoxicity due to its higher affinity to human lymphocytes
and its extended half-life [7,8]. Notwithstanding its
higher immunosuppressive quality, rabbit ATG was
inferior to horse ATG as first-line treatment for
SAA, with lower rates of hematological response and
survival [9,10]. In BMT, rabbit ATG has been used
in the preparative regimen to reduce the incidence of
graft-versus-host disease (GVHD), particularly in unrelated BMT; however, its use has been associated with
an increase in infectious complications and nonrelapse
mortality [11-15].
As horse and rabbit ATG preparations have
different biological and clinical properties, we have
Biol Blood Marrow Transplant 18:1876-1882, 2012
speculated if these drugs are interchangeable in the
preparative regimen for matched related BMT in
SAA. Therefore, we have retrospectively compared
the outcomes of patients with SAA who received either
Cy plus rabbit ATG or Cy plus horse ATG as the conditioning regimen for HLA-identical sibling BMT.
Conditioning Regimen in Aplastic Anemia
1877
fluconazole, and patients in the Cy plus rabbit
ATG group received fluconazole (60%), caspofungin
(25%), or voriconazole (15%). Granulocyte colonystimulating factor was administered only to patients
with neutropenia and life-threatening infections.
Endpoints and Definitions
PATIENTS AND METHODS
Eligibility
All patients with SAA submitted to an HLAidentical sibling BMT between June 1995 and September 2011 at the Brazilian National Cancer Institute
were identified. Exclusion criteria were abnormal cytogenetics, positive diepoxybutane chromosomal
breakage test, presence of paroxysmal nocturnal hemoglobinuria clone with clinical manifestations, previous invasive fungal disease (IFD), conditioning
regimens without ATG, and use of peripheral blood
hematopoietic stem cells. The study was approved by
the local ethics committee and was in accordance
with the Declaration of Helsinki.
Conditioning Regimens and GVHD Prophylaxis
Conditioning with Cy (50 mg/kg on days 25 to
22) plus horse ATG (lymphoglobulin 30 mg/kg on
days 25 to 23) was performed from June 1995 to October 2004. Due to the unavailability of the horse preparation in Brazil, rabbit ATG (thymoglobulin 2 mg/kg
on days 24 to 21) plus Cy at the same dose has become
the current preparative regimen since November 2004.
All patients received GVHD prophylaxis with cyclosporine and short-course methotrexate, which has
not changed during the study period. Cyclosporine
was adjusted to target a serum level between 200 and
400 ng/mL and discontinued 12 months after BMT
whenever possible.
Supportive Care and Infectious Prophylaxis
Transplantations were performed in sealed single
rooms with high-efficiency particulate air filters and
positive air pressure. Antiviral prophylaxis consisted
of acyclovir from conditioning until 1 year posttransplantation. Weekly cytomegalovirus (CMV) pp65
antigenemia was performed from neutrophil engraftment until day 1100 or beyond in patients with prolonged systemic immunosuppression. Ganciclovir
was used as preemptive therapy in cases with positive
antigenemia. Epstein-Barr virus (EBV) PCR was not
routinely performed, except in cases with clinical suspicion of posttransplantation lymphoproliferative disorder (PTLD). Antifungal prophylaxis was started
after conditioning until neutrophil engraftment or beyond in cases with extended immunosuppression, as
follows: patients in the Cy plus horse ATG received
The variables analyzed were neutrophil and platelet engraftments, acute graft-versus-host disease
(aGVHD) and chronic GVHD (cGVHD), CMV
reactivation, and disease until day 1100, IFD until
day 1100, PTLD, chimerism evolution, graft rejection, and autologous recovery.
Neutrophil engraftment was defined as the first
of 3 consecutive days with a neutrophil count $0.500
109/L, and platelet engraftment as the first of 7 consecutive days with a platelet unsupported count $20 109/L. Cases of aGVHD and cGVHD were diagnosed
and classified according to the 1994 consensus conference and the National Institutes of Health report, respectively [16,17]. CMV reactivation was defined as
the presence of one or more positive cells on CMV
pp65 antigenemia assay, and CMV disease was
defined as the combination of symptoms and/or signs
secondary to tissue lesion with detection of the virus
[18]. Diagnosis of IFD was based on the criteria by
the European Organization for Research and Treatment of Cancer/Mycoses Study Group, with the exclusion of possible IFD from analysis [19]. PTLD
diagnosis was based on the combination of a proper
clinical picture and EBV detection on the involved tissue [20]. Graft rejection and autologous recovery were
specified as previously defined [21]. Chimerism was
monitored with PCR-based analysis of variable numbers of tandem repeats in 90.9% and 100% of patients
in the Cy plus horse ATG and Cy plus rabbit ATG
groups, respectively, and cytogenetic analysis was performed in the remaining cases. Patients were classified
in 3 categories regarding chimerism evolution: full donor chimerism in cases without evidence of recipient
cells any time after BMT; transient mixed chimerism
in cases with mixed populations of donor and recipient
cells with later conversion to full donor chimerism;
and stable mixed chimerism in patients with continuous mixed chimerism.
Statistical Analysis
The chi-square or Fisher exact test were used to
compare categorical variables, and the MannWhitney nonparametric test was used for continuous
variables. Neutrophil and platelet engraftments,
aGVHD and cGVHD, IFD, and CMV reactivation
were analyzed as time-to-event outcomes with death
by other causes treated as a competitive event. Patients
who did not develop aGVHD, IFD, or CMV reactivation at day 1100 were censored at that point in time.
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E. H. Atta et al.
Biol Blood Marrow Transplant 18:1876-1882, 2012
Table 1. Comparison of Baseline Characteristics According with the Preparative Regimen
Cy Plus Horse ATG (N 5 20)
Age (years), median (range)
Male gender
VSAA at diagnosis
Previous ATG
BMT as first-line treatment
Interval diagnosis-BMT (days), median (range)
Pre-BMT hematologic parameters
ANC (109/L), median (range)
ALC (109/L), median (range)
Less than 20 units of RBC before BMT
Serum ferritin before BMT (mg/dL), median (range)
Female donor
Gender mismatch
ABO match
CMV seropositive donor
Nucleated cell dose (108/Kg), median (range)
G-CSF before day +15
20 (4-48)
12 (60%)
6 (30%)
2 (10%)
6 (30%)
170.5 (49-2659)
0.392 (0.068-2.623)
1.387 (0.170-8.356)
8 (40%)
1562 (420-7564)
9 (45%)
7 (35%)
12 (60%)
13 (65%)
3.40 (1.16-5.40)
4 (20%)
Cy Plus Rabbit ATG (N 5 20)
21.5 (7-57)
11 (55%)
4 (20%)
5 (25%)
7 (35%)
149 (56-1106)
0.510 (0.021-1.544)
1.764 (0.455-6.013)
12 (60%)
1215 (187-3485)
7 (35%)
10 (50%)
11 (55%)
14 (70%)
2.49 (1.01-5.15)
7 (35%)
P Value
.90
.75
.46
.40
.74
.70
.31
.16
.20
.22
.51
.33
.75
.74
.02
.28
Cy indicates cyclophosphamide; ATG, antithymocyte globulin; VSAA, very severe aplastic anemia; BMT, bone marrow transplantation; ANC, absolute
neutrophil count; ALC, absolute lymphocyte count; CMV, cytomegalovirus; G-CSF, granulocyte colony-stimulating factor.
The proportional hazards model of Fine and Gray was
used to compare cumulative incidence rates between
the groups, based on the tutorial by Scrucca et al.
[22]. Overall survival was measured from the date of
transplantation to death or last follow-up and analyzed
with the Kaplan-Meier method with comparisons using the log-rank test. Patients submitted to a second
BMT were censored at the time of the second BMT,
except for survival analysis. All P values were 2-sided,
with P \ .05 indicating statistical significance. Registration and analysis of data were conducted using
IBM SPSS version 15 software (IBM, Armonk, NY).
Cumulative incidence and the Fine and Gray test
were estimated using R-project version 2.13.1, the R
Project for Statistical Computing, 2011 (http://
www.r-project.org/).
RESULTS
Comparison of Baseline Characteristics
According to the Preparative Regimen
Among the 40 patients with SAA who were eligible
for this study, 20 received Cy plus horse ATG and 20
received Cy plus rabbit ATG as the preparative regimen. As shown in Table 1, except for a difference in
the nucleated cell dose, all other baseline parameters
were comparable between the groups.
Graft-versus-Host Disease
The day 1100 probability of aGVHD grades
II-IV was 35.2% (95% confidence interval [CI],
13.8%-57.7%) and 0% (95% CI, not applicable) in
patients receiving horse ATG and rabbit ATG,
respectively (P 5 .009) (Figure 1A).
The 3-year cumulative incidence of moderatesevere cGVHD was 34% (95% CI, 11.5%-58.2%)
and 0% (95% CI, not applicable) in recipients of horse
and rabbit ATG, respectively (P 5 .04) (Figure 1B). As
expected, patients with previous aGVHD grades II-IV
were more likely to develop moderate-severe cGVHD
(odds ratio, 66.0; 95% CI, 4.8-902.1; P 5 .02).
Infectious Complications
The day 1 100 probability of proven/probable
IFD was 5.5% (95% CI, 0.3%-23.0%) in recipients
of horse ATG and 31.2% (95% CI, 12.1%-52.7%) in
recipients of rabbit ATG (P 5 .04) (Figure 1C). The
IFD diagnosed in patients conditioned with rabbit
ATG were invasive aspergillosis (n 5 2), disseminated
fusariosis (n 5 2), and invasive candidiasis (n 5 2), with
a median time from BMT to diagnosis of IFD of 8 days
(range, 23 to 29 days). Only 1 case of IFD was observed in the Cy plus horse ATG group, in a patient
who developed disseminated fusariosis on day 114.
The day 1100 cumulative incidence of CMV reactivation was similar between patients conditioned with
horse and rabbit ATG, 76.4% (95% CI, 46.0%91.1%) and 76.4% (95% CI, 46.0%-91.1%), respectively (P 5 .36) (Figure 1D). However, the median
time from BMT to CMV reactivation was shorter in
recipients of rabbit ATG (40 versus 50 days; P 5
.02). Only 1 case of CMV disease was observed in a patient conditioned with Cy plus rabbit ATG who later
developed pneumonitis.
Hematopoietic Recovery, Chimerism Evolution,
and Rejection
No statistically significant difference in the CI of
neutrophil engraftment on day 128 was observed
between the groups: 100% (95% CI, not applicable)
with Cy plus horse ATG and 93.8% (95% CI,
52.5%-99.3%) with Cy plus rabbit ATG (P 5 .78).
The same is true for platelet engraftment on day 128:
82.1% (95% CI, 51.0%-94.4%) in recipients of horse
Biol Blood Marrow Transplant 18:1876-1882, 2012
Conditioning Regimen in Aplastic Anemia
1879
Figure 1. Cumulative incidence curves according to the preparative regimen: cyclophosphamide (Cy) plus horse antithymocyte globulin (ATG) and Cy
plus rabbit ATG. Day 1100 probability of grades II-IV acute graft-versus-host disease (aGVHD) (A); cumulative incidence of moderate-severe chronic
GVHD (cGVHD) after bone marrow transplantation (BMT) (B); day 1100 probability of proven/probable invasive fungal infection (C); and day 1100
probability of cytomegalovirus (CMV) reactivation (D).
ATG and 51.8% (95% CI, 25.6%-72.8%) in recipients
of rabbit ATG (P 5 .28). By contrast, the median
absolute lymphocyte count (ALC) was lower in patients
conditioned with rabbit ATG in comparison
with horse ATG on days 1 30 (0.360 versus 0.814 109/L; P 5 .01, respectively) and 190 (0.744 versus
1.330 109/L; P 5 .006, respectively). This difference
was not statistically significant on days 160, 1120, and
1180 (Figure 2A).
Chimerism assessment was available in 26 of the 30
patients who survived beyond day 1100 (86.7%). The
distributions of full donor, transient mixed, and stable
mixed chimerism were different between patients conditioned with horse ATG (81.8%, 0%, and 18.2%, respectively) and rabbit ATG (13.3%, 6.7%, and 80%,
respectively) (P 5 .002). A trend toward an inferior median ALC was observed in patients with mixed
chimerism in comparison with those with full
donor chimerism on days 1 30 (0.478 versus 0.770 109/L; P 5 .07), 160 (0.745 versus 1.031 109/L;
P 5 .03), and 190 (0.809 versus 1.270 109/L; P 5
.07) (Figure 2B). Only 2 cases of graft rejection were
noticed: 1 primary graft rejection in the Cy plus rabbit
ATG group and 1 secondary graft rejection in the
Cy plus horse ATG group. No case of autologous
recovery was observed. The 2-year probability of interruption of calcineurin inhibitor (CNI) was higher
in recipients of horse ATG: 85.2% (95% CI,
45.3%-96.8%) versus 48.1% (95% CI, 11.7%77.9%; P 5 .001). The median time to interruption
of CNI was longer in patients conditioned with
rabbit ATG (574 versus 372 days; P 5 .004).
Survival and Mortality
The median follow-up was different between the 2
preparative regimens: 1660 days (range, 7-5139 days)
for the Cy plus horse ATG group and 271 days (range,
13-1762 days) for the Cy plus rabbit ATG group (P 5
.04). The day 1100 mortality rate was similar between
recipients of horse and rabbit ATG: 25% (95% CI,
8.7%-45.4%) and 25% (95% CI, 8.7%-45.4%), respectively (P 5 .87). Likewise, the 1-year survival
was similar between the 2 regimens: 65% in the Cy
plus horse ATG group and 63.3% in the Cy plus rabbit
ATG group (P 5 .87).
The main cause of death was GVHD-related
complications in recipients of horse ATG (4 of 10: 2
with aGVHD and 2 with cGVHD) and infectiousrelated in recipients of rabbit ATG (4 of 8: invasive
fusariosis in 2 patients, aspergillosis in 1, and respiratory syncytial virus pneumonia in 1). Only 1 case of
PTLD was observed in a patient conditioned with
Cy plus horse ATG.
DISCUSSION
Our study demonstrates that horse and rabbit
ATG are not interchangeable when used with Cy in
the conditioning regimen for SAA. We observed that
the use of horse ATG was associated with a more efficient donor lymphocyte engraftment, as shown by the
higher ALC at different time points and the higher
proportion of patients with full donor chimerism.
Consequently, this was translated into higher rates of
1880
E. H. Atta et al.
Biol Blood Marrow Transplant 18:1876-1882, 2012
Figure 2. Evolution of the median absolute lymphocyte count (ALC). Evolution of the median ALC according to the preparative regimen: cyclophosphamide (Cy) plus horse antithymocyte globulin (ATG) and Cy plus rabbit ATG (A); and evolution of the median ALC in patients with full donor and
mixed chimerism (B). Asterisks denote significant differences between the groups (P \.05 on the basis of the Mann-Whitney nonparametric test).
aGVHD and cGVHD, with 4 deaths related to this
complication. On the other hand, the use of rabbit
ATG was associated with higher rates of infectious
complications, with 3 deaths related to this complication. The net result was that the 1-year probability of
survival was similar between the 2 groups.
The observed high rates of GVHD in our patients
conditioned with Cy plus horse ATG were similar to
previous studies [4-6], as was the protective effect of
rabbit ATG against GVHD [11-13]. However, to
our knowledge, our study is the first to report the
distinct effects of horse and rabbit ATG preparations
on the incidence of GVHD after matched related
BMT for SAA.
Another remarkable finding of our study was the
high rate of infectious complications, notably IFD,
in patients conditioned with Cy plus rabbit ATG.
The day 1100 CI of IFD was higher in recipients of
rabbit ATG, CMV reactivation occurred earlier, and
infection-related mortality was the main cause of death
in these patients. All IFD in the group conditioned
with rabbit ATG occurred before day 130, a period
in which neutropenia is the major risk factor for IFD
[23]. The 28-day probability of neutrophil engraftment was similar between the 2 groups. By contrast,
the median ALC at day 130 was significantly lower
in the rabbit ATG group. Lymphopenia was identified
as an independent risk factor for early IFD (ie, before
day 140, in allogeneic BMT) [24]. Therefore, the
high incidence of infectious complications after rabbit
ATG conditioning may be related to the slow recovery
of CD81 lymphocytes, which is not observed after
horse ATG conditioning [25]. Alterations in other
lymphocyte subtypes may also be related to the higher
infectious complications observed after conditioning
with rabbit ATG.
In the present study, we observed a high incidence
of mixed chimerism after conditioning with Cy plus
rabbit ATG, which is probably related to the reducedintensity nature of the SAA preparative regimens based
Biol Blood Marrow Transplant 18:1876-1882, 2012
on Cy plus ATG and the marked T cell depletion of the
graft promoted by rabbit ATG. This hypothesis is
further supported by the lower median ALC in our patients with mixed chimerism compared with those with
full donor chimerism. The high incidence of mixed chimerism after rabbit ATG conditioning promoted the
extended use of CNI, because of the concerns related
to the increased risk of late graft failure after the withdrawal of immunosuppression [21,26]. The small
proportion of patients with late graft failure observed
hampered any analysis of the association between
mixed chimerism and late graft failure. However, an
increase in the occurrence of late graft failure is
anticipated with the extended follow-up and the withdrawal of CNI in recipients of rabbit ATG.
Our study suffers from various limitations, the
most important being the small sample size and the
retrospective nature of the study. The small sample
size limited the analysis by increasing the possibility
of beta error and also hampered multivariate analysis.
Another limitation is that the 2 groups were not contemporary. Different standards in terms of supportive
care may have occurred. In addition, since the incidence of IFD, especially those caused by molds, may
be influenced by environmental factors, with different
incidence rates in different periods, we cannot exclude
the possibility that the higher incidence of IFD in the
rabbit ATG group could be because of this fact.
Despite these limitations, the different outcomes
we observed in the 2 groups are significant. Furthermore, the probability of running a prospective trial
comparing these ATG preparations for related BMT
in SAA is very low, because of the slow accrual of
SAA patients for matched BMT and the unavailability
of horse ATG in the majority of the countries.
As pointed out, the protective effect of rabbit
ATG against GVHD was counterbalanced by the
high incidence of infectious complications. Therefore, approaches to reduce the rate of complications
related to conditioning with rabbit ATG should be
pursued. Potential areas to be explored include the
use of antimold prophylaxis or active monitoring
with biomarkers (such as serum galactomannan) in
periods at greater risk, as well as the administration
of smaller doses of rabbit ATG, as reported in other
settings [13-15]. In addition, the administration of
rabbit ATG apart from bone marrow infusion could
partially reduce the T cell depletion of the graft
and, accordingly, the deleterious effects of rabbit
ATG on infectious complications and on the
acquisition of full donor chimerism. Finally,
thymoglobulin, the rabbit ATG preparation used in
our patients, seems to be more immunosuppressive
than ATG-Fresenius, and this may also affect the
outcomes [27].
In summary, our results suggest that horse and rabbit ATG preparations have different biological and
Conditioning Regimen in Aplastic Anemia
1881
clinical properties, as already demonstrated for firstline immunosuppression in SAA [9,10]. These ATG
preparations should not be used interchangeably in
the preparative regimen of matched sibling BMT in
SAA, and rabbit ATG is associated with lower rates
of aGVHD and cGVHD but higher rates of
infectious complications and mixed chimerism in
comparison with horse ATG.
ACKNOWLEDGMENTS
Financial disclosure: No support in the form of
grants, equipments, or drugs was received for this
study either from the government or from private
companies.
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